The skin is the largest organ of the body and is composed of the epidermis and dermis. The most important function of the skin is to provide the essential physical and water permeability barrier. The epidermis is a continuously regenerating tissue, which differentiates to produce a mechanical and water permeability barrier, thus making possible a terrestrial existence. This barrier is established in the epidermis by a precisely regulated keratinocyte differentiation program that results in distinct epidermal layers. The structure of the epidermis is maintained by a finely tuned balance between keratinocyte proliferation and differentiation, which results in a multilayer structure consisting of basal, spinous, granular, and cornified layers.
The innermost basal layer, which is in contact with the basement membrane, is composed of a single layer of undifferentiated keratinocytes with proliferative potential. The spinous layer consists of non-proliferating keratinocytes in an early differentiation stage with progressive maturation as the cells move from suprabasal layers outward. Spinous differentiation is followed by late differentiation in the granular layer and terminal differentiation in the outermost cornified layer (see FIG. 1). Once committed to differentiation, the cells in the basal layer lose their proliferative potential and move toward the terminally differentiated cornified layer. Despite intense investigation and data implicating elevated extracellular calcium levels, 1,25-dihydroxyvitamin D3 and other molecules, the exact mechanisms by which the keratinocyte differentiation process is initiated and regulated remain unclear.
The precise regulation of differentiation in the epidermis is crucial for proper stratification and barrier formation to occur. Epidermal homeostasis is maintained in part by orchestrating the correct expression of genes in keratinocytes at each stage of differentiation. Alterations in this differentiation program can result in skin disorders, such as psoriasis, eczema, atopic dermatitis, skin cancers, such as squamous and basal cell carcinoma, and other conditions of the skin characterized by unregulated cell division.
Thus, any upset in the balance of skin cell proliferation and differentiation signals can result in various disorders or other undesirable skin conditions. While an over-stimulation of keratinocyte proliferation may lead to hyperproliferative skin conditions, such as those mentioned above (i.e. psoriasis and various non-melanoma skin cancers), under-stimulation of keratinocyte proliferation may result in a situation of reduced growth, such as that characterized by aging skin (skin cell senescence) or skin that has been damaged. Thus, treatments directed at reducing and/or inhibiting proliferation of keratinocytes would be useful for treating conditions characterized by hyperproliferation of skin cells. Likewise, treatments for increasing proliferation of keratinocytes would be useful to improve the condition of aging or damaged skin, where new growth is slowed, and/or to accelerate wound healing. Particularly beneficial treatments would provide the ability to treat both conditions simultaneously or as needed; however no such treatments are currently available.
Accordingly, there is a need for new and effective treatments for conditions and/or diseases related to an over- or under-proliferation of skin cells. There is also a need for ways to modulate keratinocyte proliferation and/or behavior. In particular, there is a need for new methods and treatments to normalize keratinocyte proliferation.